PROJECT SUMMARY One of the biggest challenges to treating disease is the fact that individuals carrying the same pathogenic mutation can present with different disease outcomes. It is increasingly recognized that this variation can arise, in large part, due to genetic background differences of each individual. In some cases, this genetic variation appears to be more important than the underlying causative mutation. In order to truly understand how genetic variation interacts with disease causing mutations, laboratory disease studies need to take into account genetic variation. We are applying this approach to the endoplasmic reticulum (ER) stress response. The ER is a large organelle responsible for the synthesis, maturation, and delivery of proteins responsible for a variety of essential functions. ER stress occurs when misfolded proteins accumulate in the lumen of the ER. If left unresolved, cell death occurs, followed by disease. The cell responds to ER stress with the unfolded protein response (UPR). The UPR initiates a very large transcriptional response that is aimed at clearing misfolded proteins from the ER. ER stress is an important component to a number of common and rare diseases, including diabetes and neurodegenerative disorders. Importantly, many studies are now showing that pharmacological or genetic modification of the ER stress response can alter the outcome of many diseases. We hypothesize that genetic variation in the ER stress response is an important contributor to variability in disease. In order to test this, we need to understand the nature and mechanism by which ER stress varies among individuals. We utilize a number of tools in mouse and Drosophila to understand the role of genetic variation. We have recently demonstrated that the ER stress response and outcomes of disease of the ER stress response are incredibly variable and complex across individuals and genetic backgrounds. Our long term goal is to understand how genes and genetic variants interact to produce such a variable response. To do this, we will focus on two areas in this proposal: 1) Uncover the genetic architecture underlying genetic variation of the ER stress response in the mouse. We propose a number of studies aimed at understanding this at the genome-wide level, gene level, and SNP level; and 2) understand how genetic modifiers influence the phenotypic outcome of diseases of the ER stress response. Knowing how genetic variation impacts a critical disease-relevant pathway, like ER stress, will assist in designing personalized therapies that might better treat the individual patient.